ABSTRACT A large number of people living with HIV develop dementia and cognitive dysfunction often referred as HIV-associated neurocognitive disorder (HAND). The molecular and cellular mechanisms responsible for HAND are not well understood, but evidence suggests many similarities with Alzheimer's disease (AD) and related neurodegenerative disorders (NDs). Indeed, various reports have shown that HIV-infected people develop neuropathological features characteristic of AD, including deposition of amyloid-beta (A?) plaques and neurofibrillary tangles composed by phosphorylated-Tau (pTau). However, it is unclear whether these abnormalities are associated specifically with HIV infection and play a role in the neurological abnormalities observed in patients affected by HAND. A major problem to understand the molecular mechanisms implicated in the impact of HIV infection in brain degeneration is the lack of appropriate models to study the effect of HIV in the human brain and the interaction with pathological processes implicated in NDs. The major goal of this project is to comprehensively study the presence of misfolded protein aggregates in the brain and biological fluids of HIV-infected people, with or without HAND and also in relationship to treatment with combination antiretroviral therapy (cART). Our working hypothesis is that HIV infection or treatment with cART initiates events that promote the misfolding and early oligomerization of the proteins prone to aggregate in NDs and/or reduces the clearance pathways that normally eliminate these abnormally folded proteins. To test this hypothesis, we propose the following specific aims: (1) Detection and characterization of misfolded protein aggregates in the brain of HIV-infected patients. (2) Detection of misfolded protein aggregates in biological fluids of HIV-infected patients to attempt development of a biochemical assay to help HAND diagnosis and monitor its progression. (3) Development of a novel in vitro model to study the effect of HIV infection in brain alterations using lab-generated brain-like cerebral organoids. The findings generated in this project may contribute to enlighten the putative role of misfolded protein aggregates in the neurological abnormalities induced by HIV infection and understand the potential interaction between AD and related NDs with the pathogenesis of HAND. This project may also contribute to develop a novel method for biochemical diagnosis of HAND, and relevant model systems to study the CNS effect of HIV infection.